What’s New in Research – May 2017

The survival of the human species in the face of high rates of genetic mutations has remained an important problem in evolutionary biology. While mutations provide a source of novelty for the species, a large fraction of these genetic changes can also be damaging. A newborn human is estimated to have ~70 new mutations that the parents did not have. In a project conducted by Brigham and Women’s Hospital research geneticist Shamil Sunyaev, PhD, and University of Michigan professor Alexey Kondrashov, PhD, scientists studied natural selection in humans.

Their findings are published in a new paper in Science, where they report that, as a species, humans are able to keep the accumulation of damaging mutations in check because each additional mutation that’s added to a genome causes larger, and larger consequences, decreasing an individual’s ability to pass on genetic material.

A damaging mutation is one that likely interferes with the biological function that a gene has for the organism. The researchers studied population samples from Europe, Asia and Africa and found a significant depletion of individuals carrying a large number of highly damaging mutations overall. They inferred that if a new mutation occurs in a genome that already contains many damaging mutations, it has a stronger effect than if it occurred in a genome with just a few other damaging mutations. Thus, the more damaging mutations a genome carries, the less likely that individual will be able to contribute progeny to the next generation.

“Our study suggests that natural selection against highly damaging genetic mutations is ongoing in humans, and that it is aided by synergistic interactions between different parts of the human genome,” said Sunyaev.

This observation is general and is not limited to the human species. The same effect was independently observed in fruit flies.

The findings also help explain another long-standing conundrum in evolutionary biology, that of the evolutionary maintenance of sexual reproduction. Because sex shuffles two genomes together, it can generate some genomes with very few mutations, and other genomes with very many mutations every generation. If damaging mutations in a genome behave synergistically, genomes with a high number of damaging mutations are then very unlikely to leave progeny. Evolutionary theory, thus, holds that sexual reproducers may be more successful than asexual reproducers because they are able to purge multiple damaging mutations from the population with single genetic deaths post sex-induced genetic remixing. This is precisely what is observed in this study.

“By showing that sexual reproducers, such as humans and fruit flies, have a much lower rate of individuals with a large number of highly damaging mutations, our study provides support to theories that suggest that sex has an evolutionary advantage in a deterministic sense,” said lead author Mashaal Sohail, PhD candidate in systems biology at Harvard University “that is to say, sex had to come about in a species such as our own to allow for more effective natural selection because the mutation rate is too high to sustain otherwise.”

This work was conducted at Harvard Medical School’s Department of Biomedical Informatics and Brigham and Women’s Hospital’s Division of Genetics in collaboration with the Institute for Information Transmission Problems (Kharkevich Institute) of the Russian Academy of Sciences in Russia, and the Department of Neurology and Neurosurgery at the University Medical Center Utrecht in the Netherlands.

This project was supported by the National Institutes of Health and by the Russian Science Foundation.

Nearly 1 in 3 Drugs Found to Have Safety Concerns after FDA Approval
How often are safety concerns raised about a drug after it’s been approved by the FDA? Nicholas Downing, MD, of the Department of Medicine, and colleagues have found that for drugs approved between 2001 and 2010, nearly 1 in 3 had a postmarket safety event. The team defines postmarket safety events as those that lead to either withdrawal from the market due to safety concerns, a boxed warning or FDA issuance of a safety communication. They found that of 222 novel therapeutics the FDA approved during this time period, three were withdrawn, 61 received boxed warnings and 59 elicited safety communications. The team’s findings are published in JAMA.

“The fact that so many new safety risks are being identified after FDA approval indicates that the FDA is taking its responsibility of ensuring the safety of new drugs throughout their lifetime seriously,” said Downing, lead author of the study. “However, these safety risks emerge, on average, four years after approval. This means that many patients are exposed to these medications before the risks become clear.”

The team found that three drugs had been withdrawn from the market over an average follow-up period of 11.7 years. Boxed warnings, which are issued when new, life-threatening risks are identified, were issued for 61 drugs, including antipsychotics, SSRIs (selective serotonin reuptake inhibitors) and a class of drugs for the treatment of autoimmune disease. Safety communications, which are issued when new, serious risks are identified, were issued for 59 drugs, including drugs for migraine, erectile dysfunction and diabetes.

Postmarket safety events were significantly more frequent among biologics, therapeutics indicated for the treatment of psychiatric disease, those receiving accelerated approval and those with near-regulatory deadline approval. Events were significantly less frequent among drugs with regulatory review times less than 200 days.

“This analysis highlights that there is residual uncertainty about the risks and benefits of new drugs at the time of approval, thereby demonstrating the need for all stakeholders engaged in the drug development process to commit to the generation of clinically useful information both before and after regulatory approval,” said Downing.

Support for this study was provided in part by The Pew Charitable Trusts, a National Heart, Lung, and Blood Institute Cardiovascular Outcomes Center Award, the National Institute on Aging and by the American Federation for Aging Research through the Paul B. Beeson Career Development Award Program.

When the kidneys – vital organs for filtering the body’s entire blood supply – become injured, it can set in motion an unfortunate chain of events that leads to a decline in health. Sometimes, in response to chronic injury, the body begins an aberrant repair process known as fibrosis, in which normal fibroblast cells transform into myofibroblasts, proliferate out of control, migrate and form scar tissue. Once scar tissue begins to form, functional cells begin to die, and the scar tissue multiplies. Investigators have been looking for a way to break this cycle, and new findings indicate that a gene known as SMOC2 may point the way to a new intervention that could prevent this cascade of events.

Previous studies by investigators at Brigham and Women’s Hospital had identified SMOC2 as a protein that was highly upregulated in the kidneys of mice with fibrosis. In a new study published in JCI Insight, investigators report that increasing SMOC2 in the kidney helped initiate and continue the progression of kidney fibrosis, while tamping down SMOC2 prevented it. To test this, researchers overexpressed SMOC2 in a mouse model of kidney fibrosis and performed RNA sequencing to investigate the mechanisms responsible for fibrotic development. They found that SMOC2 activated a fibroblast-to-myofibroblast transition (FMT). The team then used two approaches to “silence” SMOC2 – a genetic approach, by using SMOC2 knockout mice, and a pharmacologic approach, by administering SMOC2 siRNA. Using these approaches, researchers were successful in tamping down the protein’s production, which protected against fibrosis development.

Corresponding author Vishal Vaidya, PhD, of BWH’s Renal Division, notes that one of the exciting things about SMOC2 is that it can be detected in a patient’s urine. Now that a functional connection between the protein and kidney fibrosis is becoming clearer, SMOC2 is looking like an increasingly useful biomarker for detecting fibrosis. In addition, SMOC2 may be a promising therapeutic target for an unmet medical need.

“We want to be able to intervene before the tissue becomes severely fibrotic to the point of no return. Our investigation indicates that SMOC2 could be a key to protecting against kidney fibrosis initiation and progression,” said Vaidya.

This work was made possible through funding by the Partners Innovation Discovery Grant, Outstanding New Environmental Sciences, Innovation in Regulatory Science Award from Burroughs Wellcome Fund, the Harvard Catalyst, the National Institutes of the Health, the National Institute of Environmental Health Sciences, the Harvard Medical School Laboratory of Excellence in Systems Pharmacology and the Giovanni Armenise-Harvard Foundation.

More than half of older American adults take a daily multivitamin supplement, but evidence of any clear health benefits is scarce. The Physicians’ Health Study II (PHS II) remains the only randomized, large-scale, long-term trial to test whether a daily multivitamin reduced cardiovascular disease risk, and researchers found that after 11 years of follow up, there was no significant difference in risk of major cardiovascular disease (CVD) events among men who took a multivitamin compared to those that took a placebo. In a new study, published this week in JAMA Cardiology, investigators examined whether multivitamins might help prevent CVD events among those in the PHS II with less nutritious diets. However, their results suggest that baseline nutritional status has no clear impact on whether a daily multivitamin affects the risk of CVD or overall mortality.

The PHS II includes more than 14,000 US male physicians over 50 years of age who have completed comprehensive food frequency questionnaires. By studying this population over time in a randomized clinical trial, the research team was able to eliminate many confounding variables. The team also had the opportunity to evaluate a wide range of dietary factors, including intake of fruits and vegetables, whole grains, nuts, dairy products, and red and processed meats, along with key nutrients such as vitamin B6, vitamin B12, vitamin D, and others. Overall, the investigators found that foods, nutrients, dietary patterns or supplement use assessed before the start of the clinical trial had no measurable influence on the effectiveness of a multivitamin on CVD risk in middle-aged and older men.

“Intuitively, many had thought that men with ‘poor’ nutritional status at baseline may benefit more from long-term multivitamin use on cardiovascular outcomes; however, we did not see any evidence for this in our recent analysis,” said corresponding author Howard Sesso, ScD, MPH, of the Division of Preventive Medicine and the Division of Aging at BWH. “Given the continued high prevalence of multivitamin use in the US, it remains critical for us to understand its role on nutritional status and other long-term health outcomes through clinical trials such as PHS II and other new research initiatives.”

Funding for this work was provided by the National Institutes of Health, Council for Responsible Nutrition Foundation, Pfizer Inc and COFAS Marie Curie Fellowship.

BiologicalAge-Predicting “Epigenetic Clock” for Studying How to Extend Lifespan

Lots of factors can contribute to how fast an organism ages: diet, genetics and environmental interventions can all influence lifespan. But in order to understand how each factor influences aging – and which ones may help slow its progression – researchers need an accurate biomarker, a clock that distinguishes between chronological and biological age. A traditional clock can measure the passage of chronological time and chronological age, but a so-called epigenetic clock can measure biological age. Epigenetic clocks already exist to reflect the pace of aging in humans, but in order to measure and test the effects of interventions in the lab, BWH investigators have developed an age-predicting clock designed for studies in mice. The new clock accurately predicts mouse biological age and the effects of genetic and dietary factors, giving the scientific community a new tool to better understand aging and test new interventions. Their results are published this week in Cell Metabolism.

To develop their “clock,” researchers took blood samples from 141 mice and, from among two million sites, pinpointed 90 sites from across the methylome that can predict biological age. (The methylome refers to all of the sites in the genome where chemical changes known as methylation take place, changing how and when DNA information is read.) The team then tested the effects of interventions that are known to increase lifespan and delay aging, including calorie restriction and gene knockouts. They also used the clock to measure the biological ages of induced pluripotent stem cells (iPSCs), which resemble younger blood.

The research team hopes that their technique will be useful for researchers who are studying new aging interventions in the lab. Currently, it can take years and hundreds of thousands of dollars to study mice over their lifespans and determine the effectiveness of a single intervention. Although it is no small feat to sequence the entire methylome, the new clock could allow for studies to be carried out much faster and on a larger scale.

“This is a new and much needed tool for studying how changes in diet, environment, genetic manipulations and more can influence health and lifespan,” said corresponding author Vadim Gladyshev, PhD, of BWH’s Division of Genetics. “Our hope is that researchers will be able to use this biomarker for aging to find new interventions that can extend lifespan, examine conditions that support rejuvenation and study the biology of aging and lifespan control.”

Funding for this work was provided by the National Institutes of Health.